Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years

Ayahuasca is a traditional Amazonian botanical brew made from Banisteriopsis caapi and Psychotria viridis; the former supplies β-carbolines (harmine, tetrahydroharmine, harmaline) that inhibit monoamine oxidase A (MAO‑A) and thereby enable the orally inactive tryptamine N,N‑dimethyltryptamine (DMT) from P. viridis to reach the brain and activate 5‑HT1A/2A/2C receptors. Previous human and animal work, plus anecdotal and observational reports from ritual users, have suggested potential therapeutic effects of ayahuasca and its alkaloids for mood and anxiety disorders and for substance dependence, and pharmacological studies have indicated an acceptable acute safety profile in healthy volunteers. However, evidence remains fragmented across animal models, small experimental human studies and observational assessments, and clinical trials are scarce. Dos Santos and colleagues therefore performed a systematic review to collect and synthesise animal and human studies up to 3 April 2015 that examined anxiolytic or antidepressive effects of ayahuasca and its isolated alkaloids (DMT, harmine, THH, harmaline). The stated aim was to evaluate the preclinical and clinical evidence supporting anxiolytic, antidepressant and related effects and to identify gaps requiring further investigation; the work combined animal models, experimental human dosing studies, observational studies of long‑term users and available clinical trials.

The investigators conducted a systematic review following PRISMA guidance. Electronic searches were run in PubMed (from 1 January 1966), LILACS (from 1 January 1982) and SciELO (from 1 January 1998) up to 3 April 2015 using the terms ayahuasca OR dimethyltryptamine OR harmine OR tetrahydroharmine OR harmaline AND anxiety OR anxiogenic OR anxiolytic OR depression OR depressive OR antidepressive OR antidepressant. Reference lists of identified papers were also handsearched and no language restrictions were applied. Predefined inclusion criteria covered animal models of anxiety or depression; experimental studies of ayahuasca administration to healthy volunteers with validated anxiety/depression measures; observational studies of ayahuasca consumers using validated scales; and clinical trials in patients diagnosed with anxiety or depressive disorder by DSM criteria. Journal articles, abstracts, letters, conference abstracts, books and book chapters were eligible; case reports, comments and editorials were excluded. Eligible participants included rodents and humans (healthy volunteers, ayahuasca consumers, or patients). Interventions comprised administration of ayahuasca or its alkaloids; comparators included placebo and established pharmacotherapies (for example, imipramine) where used. Outcomes were behavioural or biochemical measures in animals and symptom ratings in humans. Two independent reviewers screened studies with a third reviewer resolving discrepancies. Extracted data included authorship, year, design, participant characteristics, intervention and dose, outcome measures and response criteria. The resulting sample was divided into animal and human studies. The search yielded 514 references (four duplicates), 510 abstracts were screened, and 21 studies met the inclusion criteria and were included in the review. The included papers comprised 10 animal studies and 11 human studies (three experimental, seven observational, one clinical trial).

The review synthesised preclinical and human findings across several compounds and study types. Animal studies: Harmaline produced dose‑dependent effects on anxiety in mice, with low doses (5–10 mg/kg) increasing anxiety-like behaviour in the elevated plus maze and higher doses (20 mg/kg) showing anxiolytic effects; in a marble‑burying test lower doses (5–7.5 mg/kg) were associated with burying more marbles, interpreted by the authors as an anxiolytic effect in that model. Harmine showed consistent antidepressant‑like effects across forced swim test (FST) studies in mice and rats: intraperitoneal harmine (5–15 mg/kg) reduced immobility in the FST and in rats increased climbing and swimming time. Chronic harmine (5–15 mg/kg/day for 14 days) reduced immobility and altered swimming/climbing measures; higher doses increased hippocampal brain‑derived neurotrophic factor (BDNF) levels. In chronic mild stress (CMS) models, harmine reversed stress‑induced anhedonia (sucrose/sweet food consumption), normalised adrenal weight and adrenocorticotropic hormone (ACTH) changes, and modified citrate synthase activity. Several studies addressed oxidative stress and bioenergetics: acute and chronic harmine reduced lipid and protein oxidation and increased antioxidant enzyme activity (SOD, CAT) in prefrontal cortex and hippocampus, and altered creatine kinase and mitochondrial respiratory chain complex activities in a dose‑ and region‑dependent manner. One rat study of orally administered ayahuasca (5 mg/kg) decreased immobility time in the FST, while lower (2.5 mg/kg) and higher (10 mg/kg) doses did not show significant effects. Experimental human dosing: An open‑label intramuscular study of DMT (0.7 mg/kg) in 15 healthy volunteers found that 93% self‑reported feelings of relaxation. A double‑blind, placebo‑controlled intravenous DMT study in 15 volunteers administered doses from 0.04–0.4 mg/kg and reported that a non‑hallucinogenic dose (0.05 mg/kg) induced relaxation in some participants. A small study comparing oral and smoked DMT in six volunteers found oral DMT inactive while smoked DMT produced full psychoactive effects and increased positive mood. Observational studies of ayahuasca consumers: Several cross‑sectional or pre/post assessments reported reduced psychiatric symptoms and increased wellbeing after ritual ayahuasca use. In first‑time users (n=28) evaluations 1–4 days before and 1–2 weeks after ritual use showed reduced psychiatric symptoms and increased serenity; a six‑month follow‑up of 23 participants reported sustained reductions in symptoms and improved mental health and optimism. Experienced users (≥10 years, n=15) showed no evidence of mental health or cognitive problems and had reduced anxiety and depression scores. Adolescents (n=40) with repeated use had lower incidence of anxiety compared with non‑users. Long‑term Santo Daime members (n=32 and a separate cohort of 127 members with ≥15 years’ continuous use and 1‑year follow‑up) were reported to have reduced anxiety and depression symptoms and no increase in psychiatric problems; neuropsychological performance was not impaired. In a double‑blind, placebo‑controlled within‑ritual assessment of experienced Santo Daime members, questionnaires administered 1 hour after ayahuasca ingestion showed reduced panic and hopelessness but no change in state or trait anxiety. Clinical trial data: The review identified one pilot open‑label clinical trial in six inpatients with recurrent depression who received a single dose of ayahuasca. Depressive symptoms were significantly reduced from baseline at days 1, 7 and 21 as measured by the Hamilton Rating Scale for Depression (HAM‑D), the Montgomery‑Åsberg Depression Rating Scale (MADRS), and the anxious‑depression subscale of the Brief Psychiatric Rating Scale (BPRS). The authors also note subsequent work in a larger sample using single photon emission computed tomography (SPECT) to assess regional cerebral blood flow, but details from that study are not fully reported in the extracted text.

Across animal experiments, experimental human dosing studies, observational assessments of ritual users and one small clinical trial, the authors report convergent evidence that ayahuasca and its constituent alkaloids have anxiolytic and antidepressive properties. Dos Santos and colleagues emphasise that harmine and harmaline demonstrated anxiolytic and antidepressant‑like effects in rodent models, with harmine also modulating hippocampal BDNF, antioxidant enzymes and mitochondrial and energy‑metabolism markers, which suggests mechanisms beyond simple MAO‑A inhibition. The review highlights that DMT and other 5‑HT1A/2A/2C receptor agonists can modulate emotional processing and increase positive mood, and that serotonergic hallucinogens such as psilocybin and LSD show related anxiolytic and antidepressant effects in animal models and in some human experimental and clinical contexts. The authors discuss potential mechanisms including agonism at 5‑HT1A/2A/2C receptors, subsequent modulation of cortical glutamate and BDNF expression, anti‑inflammatory effects, and alterations in default mode network (DMN) function; they note empirical findings such as reduced DMN activation after acute ayahuasca and cortical thickness changes in regular users, and parallel fMRI findings from psilocybin studies. At the same time, the authors acknowledge that the mechanisms are not fully understood and that harmine’s effects may also involve regulation of cellular energy homeostasis, mitochondrial function and oxidative stress. Key limitations are explicitly acknowledged: the total number of studies was small and heterogeneous in design, dosage and outcomes; the majority of positive findings derive from rodent studies; human evidence is largely experimental or observational with small samples and potential confounding (for example, the psychosocial effects of joining a religious group among long‑term users); and only a single small open‑label clinical trial in depressed patients is available. The review therefore treats human evidence as preliminary and calls for further clinical trials to replicate and extend these findings. The authors note that the rapid antidepressant effect seen in their pilot study is of particular interest given the typical 2‑week onset of conventional antidepressants, but they refrain from definitive conclusions until larger, controlled clinical trials are completed.